Association of ARRDC3 and NFIA variants with bovine congestive heart failure in feedlot cattle

Authors: Heaton, Michael - Mike; Harhay, Gregory; BASSETT, ADAM - University Of Nebraska; CLARK, HALDEN - University Of Nebraska; CARLSON, JADEN - University Of Nebraska; JOBMAN, ERIN - University Of Nebraska; Sadd, Helen; PELSTER, MADELINE - University Of Nebraska; Workman, Aspen; Kuehn, Larry; KALBFLEISCH, THEODORE - University Of Kentucky; PISCATELLI, HEATHER - Matmacorp; CARRIE, MICHAEL - Matmacorp; KRAFSUR, GRETA - University Of Colorado; GROTELUESCHEN, DALE - Retired Non ARS Employee; VANDER LEY, BRIAN - University Of Nebraska

Submitted to: F1000Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/18/2022
Publication Date: 4/1/2022
Citation: Heaton, M.P., Harhay, G.P., Bassett, A.S., Clark, H.J., Carlson, J.M., Jobman, E.E., Sadd, H.R., Pelster, M.C., Workman, A.M., Kuehn, L.A., Kalbfleisch, T.S., Piscatelli, H., Carrie, M., Krafsur, G.M., Grotelueschen, D.M., Vander Ley, B.L. 2022. Association of ARRDC3 and NFIA variants with bovine congestive heart failure in feedlot cattle. F1000Research. 11. Article 385. https://doi.org/10.12688/f1000research.109488.1 .
DOI: https://doi.org/10.12688/f1000research.109488.1

Interpretive Summary: Bovine congestive heart failure (BCHF) in feedlot cattle has become increasingly common in the Western Great Plains of North America at moderate elevations (3000 to 4500 ft). This disease is an untreatable, complex condition involving high blood pressure in the lungs, which leads to subsequent heart failure and death. BCHF is fundamentally distinct from the “brisket disease” observed in the high elevations of the Rocky Mountains (>7000 ft), since BCHF occurs at much lower elevations where animals with brisket disease were previously sent to recover. Individual feedlot operations have reported losses from BCHF exceeding $250,000 annually, which are comparable to losses from bovine respiratory disease at similar locations. Cattle herds affected with BCHF are typically bred and managed with the aim of achieving high-quality carcasses. Consequently, reducing the impact of BCHF is a priority for the beef industry. In the present report, animals with end-stage heart failure from 30 different ranch sources were evaluated together with their healthy penmates. DNA sequence variation in two major genes (ARRDC3 and NFIA) was discovered to be associated with BCHF, and thus, these genes may play a role in disease development. Feedlot animals in this study, that were homozygous for the DNA risk markers in both genes, were 28-fold more likely to develop heart failure than those without. A DNA-based test with two markers showed 29% of diseased cattle had homozygous risk alleles in both genes, compared to less than 2.5% in similar unaffected feedlot cattle. This type of testing may be useful for identifying feedlot animals at the highest risk for BCHF in the Western Great Plains of North America. In herds suffering from BCHF, knowledge of which cattle have the highest and lowest genetic risk for disease allows producers to make informed decisions for selective breeding and animal health management.

Technical Abstract: Background: Bovine congestive heart failure (BCHF) has become increasingly prevalent among feedlot cattle in the Western Great Plains of North America with up to 7% mortality in affected herds. BCHF is an untreatable complex condition involving pulmonary hypertension that culminates in right ventricular failure and death. Genes associated with BCHF in feedlot cattle have not been previously identified. Our aim was to search for genomic regions associated with this disease. Methods: A retrospective, matched case-control design with 102 clinical BCHF cases and their unaffected penmates was used in a genome-wide association study. Paired nominal data from approximately 560k filtered single nucleotide polymorphisms (SNPs) were analyzed with McNemar’s test. Results: The most significant genome-wide association was in the arrestin domain-containing protein 3 gene (ARRDC3), followed by the nuclear factor IA gene (NFIA, mid-p-values, 1x10-8 and 2x10-7, respectively). Animals with homozygous risk alleles at either gene were approximately 8-fold more likely to have BCHF than their matched penmates without those risk alleles (CI95 = 3-17). Animals with homozygous risk alleles at both genes were 28-fold more likely to have BCHF than all others (p-value = 1x10-7, CI95 = 4-206). A linked missense variant in ARRDC3 (C182Y) represents a potential functional variant as the C182 codon is conserved among all other jawed vertebrate species observed. A DNA test with two markers showed 29% of 273 BCHF cases had homozygous risk alleles in both genes, compared to 2.5% in 198 similar unaffected feedlot cattle. This DNA test may be useful for identifying feedlot animals with the highest risk for BCHF in environments like those described here. Conclusions: Although pathogenic roles for ARRDC3 and NFIA variants associated with BCHF are unknown, their discovery facilitates classifying animals by genetic risk and allows cattle producers to make informed decisions for selective breeding and animal health management.